JAMA. 2014 Mar 12;311(10):1035-45. doi: 10.1001/jama.2014.1717.

Clinical interpretation and implications of whole-genome sequencing.

Dewey FE¹, Grove ME¹, Pan C², Goldstein BA³, Bernstein JA⁴, Chaib H², Merker JD⁵, Goldfeder RL⁶, Enns GM⁴, David SP³, Pakdaman N³, Ormond KE⁷, Caleshu C⁸, Kingham K⁹, Klein TE¹⁰, Whirl-Carrillo M¹⁰, Sakamoto K¹¹, Wheeler MT¹, Butte AJ¹², Ford JM⁹, Boxer L³, Ioannidis JP¹³, Yeung AC¹⁴, Altman RB¹⁵, Assimes TL¹⁴, Snyder M¹⁶, Ashley EA¹, Quertermous T¹.

Author information

1: Stanford Center for Inherited Cardiovascular Disease, Stanford, California2Stanford Cardiovascular Institute, Stanford, California3Division of Cardiovascular Medicine, Stanford University, Stanford, California4Stanford Center for Genomics and Personalized.
2: Stanford Center for Genomics and Personalized Medicine, Stanford, California5Department of Genetics, Stanford University, Stanford, California.
3: Department of Medicine, Stanford University, Stanford, California.
4: Department of Pediatrics, Stanford University, Stanford, California.
5: Department of Pathology, Stanford University, Stanford, California.
6: Biomedical Informatics Training Program, Stanford University, Stanford, California.
7: Department of Genetics, Stanford University, Stanford, California10Stanford Center for Biomedical Ethics, Stanford, California.
8: Stanford Center for Inherited Cardiovascular Disease, Stanford, California2Stanford Cardiovascular Institute, Stanford, California3Division of Cardiovascular Medicine, Stanford University, Stanford, California7Department of Pediatrics, Stanford University.
9: Division of Medical Oncology, Stanford University, Stanford, California.
10: Department of Genetics, Stanford University, Stanford, California.
11: Division of Cardiovascular Medicine, Stanford University, Stanford, California6Department of Medicine, Stanford University, Stanford, California.
12: Department of Pediatrics, Stanford University, Stanford, California12Division of Systems Medicine, Stanford University, Stanford, California.
13: Department of Medicine, Stanford University, Stanford, California12Division of Systems Medicine, Stanford University, Stanford, California14Stanford Prevention Research Center, Stanford, California15Department of Health Research and Policy, Stanford Unive.
14: Stanford Cardiovascular Institute, Stanford, California3Division of Cardiovascular Medicine, Stanford University, Stanford, California.
15: Department of Genetics, Stanford University, Stanford, California6Department of Medicine, Stanford University, Stanford, California16Department of Bioengineering, Stanford University, Stanford, California.
16: Stanford Cardiovascular Institute, Stanford, California4Stanford Center for Genomics and Personalized Medicine, Stanford, California5Department of Genetics, Stanford University, Stanford, California.

Abstract

IMPORTANCE:

Whole-genome sequencing (WGS) is increasingly applied in clinical medicine and is expected to uncover clinically significant findings regardless of sequencing indication.

OBJECTIVES:

To examine coverage and concordance of clinically relevant genetic variation provided by WGS technologies; to quantitate inherited disease risk and pharmacogenomic findings in WGS data and resources required for their discovery and interpretation; and to evaluate clinical action prompted by WGS findings.

DESIGN, SETTING, AND PARTICIPANTS:

An exploratory study of 12 adult participants recruited at Stanford University Medical Center who underwent WGS between November 2011 and March 2012. A multidisciplinary team reviewed all potentially reportable genetic findings. Five physicians proposed initial clinical follow-up based on the genetic findings.

MAIN OUTCOMES AND MEASURES:

Genome coverage and sequencing platform concordance in different categories of genetic disease risk, person-hours spent curating candidate disease-risk variants, interpretation agreement between trained curators and disease genetics databases, burden of inherited disease risk and pharmacogenomic findings, and burden and interrater agreement of proposed clinical follow-up.

RESULTS:

Depending on sequencing platform, 10% to 19% of inherited disease genes were not covered to accepted standards for single nucleotide variant discovery. Genotype concordance was high for previously described single nucleotide genetic variants (99%-100%) but low for small insertion/deletion variants (53%-59%). Curation of 90 to 127 genetic variants in each participant required a median of 54 minutes (range, 5-223 minutes) per genetic variant, resulted in moderate classification agreement between professionals (Gross κ, 0.52; 95% CI, 0.40-0.64), and reclassified 69% of genetic variants cataloged as disease causing in mutation databases to variants of uncertain or lesser significance. Two to 6 personal disease-risk findings were discovered in each participant, including 1 frameshift deletion in the BRCA1 gene implicated in hereditary breast and ovarian cancer. Physician review of sequencing findings prompted consideration of a median of 1 to 3 initial diagnostic tests and referrals per participant, with fair interrater agreement about the suitability of WGS findings for clinical follow-up (Fleiss κ, 0.24; P < 001).

CONCLUSIONS AND RELEVANCE:

In this exploratory study of 12 volunteer adults, the use of WGS was associated with incomplete coverage of inherited disease genes, low reproducibility of detection of genetic variation with the highest potential clinical effects, and uncertainty about clinically reportable findings. In certain cases, WGS will identify clinically actionable genetic variants warranting early medical intervention. These issues should be considered when determining the role of WGS in clinical medicine.